combination of icss and labas should be used in the ...can respir j vol 11 no 3 april 2004 221...

Can Respir J Vol 11 No 3 April 2004 221

Combination of ICSs and LABAs should be used in themanagement of patients with COPD – The pro argument

Don D Sin MD

James Hogg iCapture Centre for Cardiovascular and Pulmonary Research; Department of Medicine, Pulmonary Division, University of BritishColumbia, Vancouver, British Columbia; Institute of Health Economics, Edmonton, Alberta

Correspondence: Dr Don D Sin, James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research, St Paul’s Hospital, Room 368A,1081 Burrard Street, Vancouver, British Columbia V5Z 1Y7. Telephone 604-806-8395, fax 604-806-9274, e-mail [email protected]

THE EFFECTS OF INHALED

CORTICOSTEROID MONOTHERAPY

Airway inflammation is a prominent feature of chronic obstruc-

tive pulmonary disease (COPD), even among ex-smokers (1),

and its intensity is directly related to the severity of the under-

lying COPD (2). The inflammatory burden increases during

periods of clinical exacerbation (3-5). Predictably, use of sys-

temic corticosteroids during these episodes accelerates clinical

recovery and improves health outcomes over several months of

follow-up (6). Unfortunately, long term use of systemic corti-

costeroids is generally precluded by their toxic side effects.

Inhaled corticosteroids, on the other hand, share much of the

anti-inflammatory properties of the systemic formulations

without the side effects (7). However, their effectiveness has

been questioned and is a matter of heated debate among mem-

bers of the scientific community (8,9).

Some have argued that the inflammatory process in the

COPD airways may be resistant to corticosteroids for various

reasons. First, cells within COPD airways have reduced his-

tone deacetylase activity (10). Histone deacetylase is an

important cofactor that assists corticosteroids in deactivating

various inflammatory genes; its deficiency may, therefore,

make the inflammatory process more resistant to the effects

of corticosteroids (10). Second, corticosteroids have minimal

effects on neutrophils, which are found in abundance in the

airway lumen of COPD patients and are thought to have

some (if not a predominant) role in COPD pathogenesis

(10). Indeed, in some cases, corticosteroids may delay neu-

trophil apoptosis, which, paradoxically, could promote airway

neutrophilia.

Notwithstanding these theoretical concerns, clinical stud-

ies have demonstrated that inhaled corticosteroids can down-

regulate certain components of the inflammatory process

within COPD airways. Patel and coworkers (11), for example,

showed a marked attenuation of interleukin (IL)-6 and IL-8

production by bronchial epithelial cells from COPD patients

taking inhaled corticosteroids compared with COPD patients

not taking inhaled corticosteroids. In another experiment, six

weeks of inhaled beclomethasone (1.5 mg/day) reduced IL-8

levels by 68% in the bronchial lavage fluid of patients with

mild to moderate COPD (12). IL-8 is important in neutrophil

recruitment and chemotaxis. This may explain why, although

corticosteroids have minimal direct effects on neutrophils,

Confalonieri and coworkers (13) demonstrated a marked

reduction in the number of neutrophils in the sputum of

COPD patients after eight weeks of treatment with inhaled

beclomethasone (1.5 mg/day).

Inhaled corticosteroids have other anti-inflammatory prop-

erties. They reduce the expression of soluble intercellular

adhesion molecules, which are important molecules in effect-

ing transmigration of proinflammatory cells across the endothe-

lial surface into deeper tissues (11). They also repress mast cell

expression in the stromal layers of bronchial epithelium. For

example, three months of inhaled fluticasone therapy reduce

the subepithelial mast cell concentration by 24% (14).

Furthermore, four weeks of inhaled beclomethasone can

reduce sputum eosinophil numbers by 47% (from baseline)

(12). They also reduce inducible nitric oxide synthase-positive

and nitrotyrosine-positive cells by 40% and 39%, respectively,

from baseline levels, suggesting that, in addition to their anti-

inflammatory effects, inhaled corticosteroids may attenuate

oxidative stress within COPD airways (15).

Not surprisingly, given these biological effects of inhaled cor-

ticosteroids on the inflammatory and oxidative processes in the

airways of COPD, large, randomized, controlled trials have

demonstrated that inhaled corticosteroids have salutary effects

on clinically relevant health outcomes. A meta-analysis of data

from large, randomized studies showed that inhaled corticos-

teroids reduce clinical exacerbation rates by approximately 25%

relative to placebo among COPD patients (relative risk [RR] 0.76;

95% CI 0.72 to 0.80) (16,17). The magnitude of the risk reduc-

tion was similar between short (less than one-year) and long

(four-year) trials, suggesting that the symptomatic benefit of

inhaled corticosteroids extends to at least three to four years of

follow-up (16). The beneficial effects were more pronounced

among those with severe underlying disease (forced expiratory

volume in 1 s [FEV1] less than 50% predicted). They were not

particularly beneficial among those with an FEV1 greater than

2.0 L (17). Inhaled corticosteroids also reduced the rate of

decline in health status in COPD. For the Symptoms component

of the St George’s Respiratory Questionnaire, inhaled corticos-

teroids decelerated the rate of deterioration by over 50% (18). In

other areas of the St George’s Respiratory Questionnaire

(Activity and Impacts score), the rate of deterioration was atten-

uated by approximately one-third compared with placebo, which

represented clinically relevant changes (18). Discontinuation of

inhaled corticosteroids, on the other hand, resulted in an

increase in patient symptoms and an elevated risk of exacerba-

tions. Van der Valk and colleagues (19) demonstrated among

244 COPD patients (with a mean FEV1 of approximately 1.7 L)

©2004 Pulsus Group Inc. All rights reserved

SUMMARIES OF PAPERS PRESENTED AT THE 2003 CTS MEETING

Sin.qxd 08/04/2004 1:42 PM Page 221

that withdrawal of inhaled corticosteroids after at least four

months of therapy led to a 1.5-fold increase in clinical exacerba-

tions (RR 1.5; 95% CI 1.05 to 2.1) compared with those who

continued on with steroid therapy. Predictably, health-related

quality of life deteriorated at a much faster rate when patients

were taken off of inhaled corticosteroids compared with those

who remained on these drugs. These beneficial clinical effects

were observed in the absence of discernible changes in the rate of

descent in FEV1. This suggests that accelerated declines in lung

function may be controlled by factors other than airway inflam-

mation. Irrespective of the mechanisms involved, there is com-

pelling evidence to indicate that monotherapy with inhaled

corticosteroids improves clinical outcomes in COPD.

THE EFFECTS OF LONG-ACTING

BETA2-AGONISTS AND INHALED

CORTICOSTEROIDS

Because airflow obstruction is a prominent feature of COPD,

long-acting beta2-agonists (LABAs) were introduced with the

aim of maximizing bronchodilation in these patients. LABAs

are potent bronchodilators. They act by stimulating the adeny-

late cyclase pathways, which, in turn, increase intracellular

concentrations of cyclic adenosine monophosphate (20).

Although LABAs by themselves have weak anti-inflammatory

effects, in vitro studies suggest that they can materially amplify

the effects of corticosteroids when given as combination ther-

apy, making it possible to achieve large anti-inflammatory

effects even with relatively low doses of corticosteroids (20).

For instance, the addition of LABAs to inhaled corticosteroids

accelerates translocation of glucocorticoid receptors from the

cytoplasm into the nucleus, where they can modify the actions

of transcription cofactors, nuclear factor kappa-B and activated

protein-1 (21). LABAs also appear to increase the effective-

ness of corticosteroids in suppressing expression of adhesion

molecules such as intercellular adhesion molecule-1 (20). The

bronchodilatory effect of LABAs may also facilitate corticos-

teroid deposition into areas of the lung, wherein active inflam-

mation is present and prominent. Finally, corticosteroids can

potentiate beta2 activity by upregulating expression of beta2receptors and by preventing receptor uncoupling in response to

an inflammatory stimulus (22). Combined with an inhaled

corticosteroid, LABAs may, therefore, have additive or even

synergistic effects on airway inflammation.

Although there are fewer clinical studies of LABA and

inhaled corticosteroid combination therapy than there are for

monotherapy with inhaled corticosteroids, the data for combi-

nation therapy are, indeed, very impressive. Several high qual-

ity, randomized, controlled trials have shown that combination

therapy leads to better health-related quality of life over short

and long term follow-up periods than inhaled corticosteroids

alone (23-26). Overall, patients who received combination

therapy with inhaled corticosteroids and LABAs experienced

30%, 20% and 10% fewer clinical exacerbations (requiring

oral corticosteroids) than those who received placebo, LABA

or inhaled corticosteroid monotherapy, respectively (17).

Combination therapy improved patients’ FEV1 values by over

100 mL compared with placebo within the first year of therapy.

It was more powerful than inhaled corticosteroid or LABA

monotherapy in improving trough FEV1 (increase of

50 mL/year, 95% CI 26 mL/year to 74 mL/year compared with

inhaled corticosteroid monotherapy; increase of 34 mL/year,

95% CI 11 mL/year to 57 mL/year compared with LABA

monotherapy) (17). The beneficial effects of inhaled corticos-

teroids and LABAs, therefore, appeared to be additive, not

synergistic. Although the effect of combination therapy on

mortality remains uncertain (pending publication of larger

studies powered specifically on mortality), there is a strong sug-

gestion toward decreased mortality with combination products

(RR versus placebo 0.52; 95% CI 0.20 to 1.34). These data are

supported by an observational study by Soriano and co-workers

(27). In this carefully performed epidemiological study using

the United Kingdom General Practice Research Database, an

automated database of primary care covering approximately

3.4 million people, the investigators found that COPD patients

who received a prescription for an inhaled corticosteroid plus a

LABA within 90 days of hospital discharge were 41% less likely

to experience a combined end point of repeat hospitalization

for COPD or all-cause mortality. This effect size was larger

than that observed with each individual drug alone. Similar

data have been reported by the Lovelace Group (28) and by

Dutch investigators (28) using a similar experimental design.

CONCLUSIONS

The totality of evidence strongly indicates that combination

therapy with inhaled corticosteroids and LABAs produces

beneficial health outcomes in COPD. Combination therapy

reduces the rate of exacerbations by nearly one-third and

improves trough FEV1 by over 100 mL compared with placebo

within the first year of therapy. There are now emerging data

to suggest that combination therapy may have salutary effects

on survival. Overall, there is compelling evidence and scientific

rationale for using combination therapy in the management of

moderate to severe COPD (29).

ACKNOWLEDGEMENTS: Dr Sin is supported by a NewInvestigator Award from the Canadian Institutes of HealthResearch and a GSK/St Paul’s Hospital Foundation COPDProfessorship. Dr Sin has received honoraria for speaking engage-ments, consultative fees, and research funding fromGlaxoSmithKline and AstraZeneca.

Sin

Can Respir J Vol 11 No 3 April 2004222

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